title: Microarray and functional cluster analysis implicates transforming growth factor beta1 in endothelial cell dysfunction in a swine hemorrhagic shock model.
abstract: BACKGROUND
  Trauma leading to massive hemorrhage results in widespread tissue hypoxia, anaerobic metabolism, and production of inflammatory cytokines and oxidative molecules injurious to the vascular endothelium. Although trauma-related endothelial cell pathophysiology has been extensively studied, very little is known regarding gene transcriptional changes that occur during the event, particularly in endothelia. Thus, we employed fluorescent microarray analysis of gene transcription to elucidate critical pathways and gene products involved in endothelial dysfunction.
  
  
  METHODS
  A trauma-hemorrhage/shock (T-H/S) model mimicking the physiologic changes seen in human trauma was performed on 10 Yorkshire swine, consisting of 35% blood volume hemorrhage followed by 6 h of full resuscitation. Aortic endothelium was analyzed by microarray and functional clusters were identified through the use of Database for Annotation, Visualization, and Integrated Discovery (DAVID) software.
  
  
  RESULTS
  Injured swine developed profound acidosis, coagulopathy, massive resuscitative fluid requirements, and microscopic changes of ischemia/reperfusion injury. While 1007 transcripts were down-regulated, 529 transcripts were up-regulated. DAVID functional clustering analysis revealed 21 significantly altered biological processes that were grouped into 12 distinct functional categories. The transforming growth factor beta (TGFβ) family of genes was the most interrelated. In addition, vascular endothelial growth factor (VEGF) signaling members and leukocyte chemoattractants were also altered.
  
  
  CONCLUSIONS
  Our model identified two major signaling pathways, TGFβ and VEGF, which undergo early transcriptional changes in injured endothelial cells. Our results suggest that TGFβ and VEGF may play a crucial role in the development of endothelial cell injury leading to increased vascular permeability during shock-trauma.
authors.affiliation: Department of Surgery, Madigan Army Medical Center, Tacoma, Washington, USA.
authors.forename: Marlin Wayne
authors.initials: MW
authors.lastname: Causey
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Hoffer
authors.forename: Seth L
authors.initials: SL
authors.lastname: Miller
authors.forename: Laurel J
authors.initials: LJ
authors.lastname: Huston
authors.forename: Steve A
authors.initials: SA
authors.lastname: Satterly
authors.forename: Matthew
authors.initials: M
authors.lastname: Martin
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Stallings
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D016000:Cluster Analysis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A